We face a super-aged society today. Sarcopenia, as well as dementia, is a major problem in today's super-aged society, but an early diagnosis and prevention of muscle atrophy are long-standing problems. Sarcopenia is defined as a disease associated with a decrease in the amount of skeletal muscle. Further, in a broader sense, it is considered that sarcopenia includes a disease associated with a skeletal muscle weakness or a decline in function.
Sarcopenia is developed in skeletal muscles. The skeletal muscle is mainly composed of two fibers, i.e. slow-twitch muscle fiber and fast-twitch muscle fiber, and, in each muscle, these two fibers with a certain proportion are arranged in a mosaic-like arrangement. The slow-twitch muscle fiber has excellent, aerobic energy production ability. A contraction rate of the slow-twitch muscle fiber is low, but a tolerance to fatigue thereof is excellent. Therefore, it is considered that the slow-twitch muscle fiber is suitable for an exercise of endurance. On the other hand, the fast-twitch muscle fiber has excellent, anaerobic energy production ability, and a generated tension thereof is high. Therefore, it is considered that the fast-twitch muscle fiber is suitable for a resistance exercise.
Further, disuse muscle atrophy, motor nerve damage, cachexia, chronic obstructive lung disease, Crohn disease, type I and II diabetes, neuromuscular incurable disease, autoimmune myasthenia gravis, sarcopenic obesity, arteriosclerosis with muscle atrophy, muscle atrophy associated with cerebral vascular disease, muscle damage, muscle tissue reconstruction after external injury or surgery treatment, muscular dystrophy, or the like, is known as a disease with a change of skeletal muscle (non-patent literatures 1 to 3), and development of therapeutic agents against the above diseases have been conducted. However, an effective therapeutic agent has not been developed.
The incurable neuromuscular diseases include amyotrophic lateral sclerosis, polymyositis, Guillain-Barré syndrome, congenital myasthenia, muscular dystrophy, distal myopathy, congenital myopathy, glycogen storage disease, mitochondrial myopathy, steroid myopathy, inflammatory myopathy, endocrine myopathy, and lipid storage myopathy.
A MyHCβ-YFP knock-in mouse in which a fluorescent protein YFP is bound to myosin-heavy chain β is reported as a means for visualizing myosin-heavy chain β of a cardiac muscle (non-patent literature 4). The myosin-heavy chain β gene of a cardiac muscle is the same as a MyHCI gene of a skeletal muscle, and thus, the inventors have found that the MyHCI can be expressed in the skeletal muscle and visualized (non-patent literature 5). Hereinafter, MyHCβ-YFP is referred to as MyHCI-YFP. Further, the inventors prepared a knock-in mouse, wherein a fusion protein in which a fluorescent protein Sirius is bound to myosin-heavy chain IIa of a skeletal muscle, and a fusion protein in which a fluorescent protein mCherry is bound to myosin-heavy chain IIb of a skeletal muscle are knocked-in, and reported that a composition shift of muscle fibers caused by training can be visualized (non-patent literature 5). However, the knock-in mouse is not a model mouse of a skeletal muscle disease, and thus, it is not used for developing therapeutic agents.